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Page 242 Van Der Steen et al. Cancer Drug Resist 2018;1:230-49 I http://dx.doi.org/10.20517/cdr.2018.13

A third strategy is to reconsider combinations of anti-signaling drugs (including anti-angiogenesis
drugs) with standard therapies such as gemcitabine, pemetrexed, cisplatin, taxanes and radiation. These
combinations should be designed taking into account the effect of these standard therapies on signaling
pathways and the tumor surroundings. These drugs usually activate the AKT pathway as a survival
[154]
mechanism . Both in experimental systems and in patients it has been demonstrated that inhibition of
AKT or EGFR can neutralize the AKT activation and enhance efficacy of standard drugs. For instance in
several NSCLC models erlotinib increased the efficacy of pemetrexed [155] , while inhibition of AKT with
perifosine enhanced the efficacy of the platinum analog satraplatin [156] . MK2206 enhanced the effect of
radiation alone [157] or in combination with gemcitabine and radiation (El-Naggar, unpublished results).
Unfortunately, the current AKT inhibitors (e.g., MK2206, perifosine) were not sufficiently effective in
patients, but several novel inhibitors are under development.

Finally, the implementation of liquid biopsies can be helpful, both for monitoring, e.g., the percentage of
mutated cells in a tumor over time and for screening the occurrence of mechanisms of resistance during
the treatment (as already approved for T790M detection). This approach can provide the treating physicians
with the necessary information to decide to either continue treatment or to switch to another strategy in
time (at the earliest sign of resistance).

The influence of drug efflux transporters and lysosomal sequestration on the intracellular concentration
and location of small molecule inhibitors should not be overlooked. This is illustrated with erlotinib
and gefitinib, which do not reach therapeutic concentrations in the brain, because of rapid efflux. Since
osimertinib readily passes the blood-brain barrier and is not effluxed, patients with brain metastases
should receive first-line treatment with osimertinib.

CONCLUSION
Identification of EGFR mutations in NSCLC and development of targeted treatment led to a revolution
in the treatment of this peculiar oncogene-driven disease. The TKIs erlotinib, gefitinib, afatinib and
osimertinib have been implemented in current clinical practice. However, the successful inhibition of
EGFR signaling pathway can be limited by different mechanisms of resistance. A very important role is
played by the T790M and C797S mutations that arise in most patients after treatment with EGFR-TKIs.
Moreover, the identification of additional resistance mechanisms by activating bypassing pathways has
taught us a lot on the intertwining of intracellular signaling pathways and gives us more possibilities to
overcome this resistance by inhibiting multiple pathways simultaneously.

The activity of TKIs can also be influenced by other resistance mechanisms such as histological
transformation, drug efflux transporters and lysosomal sequestration. The latter mechanisms need to be
taken into account for the development and testing of new TKIs, in order to prevent lower than expected
activity of these drugs in the clinical practice.

DECLARATIONS
Authors’ contributions
Original concept and writing: Van Der Steen N
Supervision and revision: Giovannetti E, Peters GJ
Writing and revision: Carbone D, Leonetti A
Supervision: Rolfo CD

Availability of data and materials
Not applicable.